Time-course microarrays reveal early activation of the immune transcriptome and adipokine dysregulation leads to fibrosis in visceral adipose depots during diet-induced obesity

BMC Genomics. 2012 Sep 4;13:450. doi: 10.1186/1471-2164-13-450.

Abstract

Background: Visceral white adipose tissue (WAT) hypertrophy, adipokine production, inflammation and fibrosis are strongly associated with obesity, but the time-course of these changes in-vivo are not fully understood. Therefore, the aim of this study was to establish the time-course of changes in adipocyte morphology, adipokines and the global transcriptional landscape in visceral WAT during the development of diet-induced obesity.

Results: C57BL/6 J mice were fed a high-fat diet (HFD) or normal diet (ND) and sacrificed at 8 time-points over 24 weeks. Excessive fat accumulation was evident in visceral WAT depots (Epidydimal, Perirenal, Retroperitoneum, Mesentery) after 2-4 weeks. Fibrillar collagen accumulation was evident in epidydimal adipocytes at 24 weeks. Plasma adipokines, leptin, resistin and adipsin, increased early and time-dependently, while adiponectin decreased late after 20 weeks. Only plasma leptin and adiponectin levels were associated with their respective mRNA levels in visceral WAT. Time-course microarrays revealed early and sustained activation of the immune transcriptome in epididymal and mesenteric depots. Up-regulated inflammatory genes included pro-inflammatory cytokines, chemokines (Tnf, Il1rn, Saa3, Emr1, Adam8, Itgam, Ccl2, 3, 4, 6, 7 and 9) and their upstream signalling pathway genes (multiple Toll-like receptors, Irf5 and Cd14). Early changes also occurred in fibrosis, extracellular matrix, collagen and cathepsin related-genes, but histological fibrosis was only visible in the later stages.

Conclusions: In diet-induced obesity, early activation of TLR-mediated inflammatory signalling cascades by CD antigen genes, leads to increased expression of pro-inflammatory cytokines and chemokines, resulting in chronic low-grade inflammation. Early changes in collagen genes may trigger the accumulation of ECM components, promoting fibrosis in the later stages of diet-induced obesity. New therapeutic approaches targeting visceral adipose tissue genes altered early by HFD feeding may help ameliorate the deleterious effects of diet-induced obesity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipokines / metabolism*
  • Adiponectin / blood
  • Adiponectin / genetics
  • Adipose Tissue, White / metabolism
  • Animals
  • Cathepsins / genetics
  • Cathepsins / metabolism
  • Chemokines / genetics
  • Chemokines / metabolism
  • Complement Factor D / genetics
  • Complement Factor D / metabolism
  • Cytokines / genetics
  • Cytokines / metabolism
  • Diet, High-Fat
  • Fibrosis / genetics*
  • Fibrosis / metabolism
  • Leptin / blood
  • Leptin / genetics
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Obesity / genetics*
  • Obesity / immunology
  • Obesity / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Resistin / blood
  • Resistin / genetics
  • Signal Transduction
  • Time Factors
  • Transcriptome / genetics*

Substances

  • Adipokines
  • Adiponectin
  • Chemokines
  • Cytokines
  • Leptin
  • Resistin
  • Cathepsins
  • Complement Factor D